This invention relates to organic compounds which inhibit lipoxygenase enzymes. It also relates to methods of inhibiting lipoxygenase enzymes in human and animal hosts in need of such treatment.
The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding 5-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LTs).
Similarly 12- and 15-lipoxygenase, convert arachidonic acid to 12- and 15-HPETE respectively. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in various disease states. For example, the LTs C.sub.4 and D.sub.4 are potent constrictors of human airways in vitro, and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction. LTB.sub.4 and 5-HETE are potent chemotactic factors for imflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheomatoid arthritic patients. Leukotrienes have also been implicated as important mediators in allergic rhinitis psoriasis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, and ischemia induced myocardial injury among others. The biological activity of the LTs has been reviewed by Lewis and Austen (J. Clinical Invest. 73,89, 1984 and by J. Sirois (Adv. Lipid Res. 21, 78, 1985).
The product 12-HETE has been found in high levels in epidermal tissue of patients with psoriasis. The lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils.
Thus, lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy arthritis, psoriasis, and inflammation. Blocking these enzymes interrupts the biochemical pathways believed to be involved in these disease states.
One of the problems associated with the development of lipoxygenase inhibitors is that many such compounds are poorly absorbed into the blood stream if administered orally. Thus, it is difficult to achieve high plasma levels. Another deficiency of many inhibitors is that even when they are absorbed, they are subject to metabolism and do not have long plasma duration. Metabolism cleaves the compounds into metabolites which are believed to have little lipoxygenase enzyme inhibition. Thus, there is a need for lipoxygenase inhibiting compounds with high plasma levels and long duration, particularly because lipoxygenase enzymes are belived to be implicated in a variety of disease states.